Hindawi Publishing Corporation

Evidence-Based Complementary and Alternative Medicine

Volume 2015, Article ID 521584, 6 pages
http://dx.doi.org/10.1155/2015/521584

Review Article
Resistance to Antibiotics and Antifungal Medicinal Products:
Can Complementary and Alternative Medicine Help Solve the
Problem in Common Infection Diseases? The Introduction of
a Dutch Research Consortium

Esther T. Kok,1,2 Miek C. Jong,3,4,5 Barbara Gravendeel,1,6

Willem B. Van Leeuwen,1 and Erik W. Baars1,3
1
University of Applied Sciences, 2333 CK Leiden, Netherlands
2
Centre for Academic Primary Care, School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK
3
Department of Healthcare and Nutrition, Louis Bolk Institute, 2972 LA Driebergen, Netherlands
4
Department of Health Sciences, Mid Sweden University, 871 31 Sundsvall, Sweden
5
National Information and Knowledge Centre on Integrative Medicine (NIKIM), Amsterdam, Netherlands
6
Naturalis Biodiversity Center, 2333 CR Leiden, Netherlands

Correspondence should be addressed to Esther T. Kok; esther.kok@bristol.ac.uk

Received 29 June 2015; Accepted 25 August 2015

Academic Editor: Cheryl Hawk

Copyright 2015 Esther T. Kok et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The increase of antibiotic resistance worldwide, rising numbers of deaths and costs associated with this, and the fact that hardly
any new antimicrobial drugs have been developed during the last decade have increased the interest in Complementary and
Alternative Medicine (CAM) therapeutic interventions, if proven safe and effective. Observational studies on clinical CAM practices
demonstrate positive effects of treatment of infections with CAM therapies (clinical effects, patient satisfaction) in combination with
small percentages of antibiotics prescription. However, Cochrane reviews and other studies demonstrate that in most instances the
quality of clinical trials on CAM treatment of infections is currently too low to provide sufficient evidence. Therefore a Dutch
consortium on (in vitro and clinical) scientific research on CAM and antibiotic resistance has been formed. The aim and objective
of the consortium is to establish an enduring partnership and to develop expertise to further develop and investigate safe and
effective CAM treatments for infectious diseases of humans (and animals). A first ongoing project on the development of safe and
effective biobased CAM antimycotics in women with (recurrent) vaginal candidiasis infection is introduced.

1. Introduction The development of generations of antibiotic-resistant

The discovery of antibiotics was one of the most significant
events in medical history and is said to have added a decade to
the life expectancy of humans [1]. Together with vaccination
and public health measures (e.g., clean water, invention, and
introduction of drainage systems and the fridge), antibiotics
were responsible for a dramatic reduction of the mortality
rate from infectious diseases. Regrettably, it seems that the
successful use of any therapeutic agent is compromised by
the potential development of tolerance or resistance to that
compound from the time it is first employed.
microbes and their distribution are the result of many years
of underuse, overuse, and misuse of antibiotics by human
applications (weak or no antibiotic policy and poor infection
control). For more than five decades the problem of how to
contain antimicrobial resistance (AMR) persists and due to
the low chance of success we are now, in the early decades
of the 21st century, facing a global issue of concern with
serious consequences: Drug-resistant infections already kill
hundreds of thousands a year globally, and by 2050 that
figure could be more than 10 million. The economic cost
will also be significant, with the world economy being hit
2 Evidence-Based Complementary and Alternative Medicine
by up to $100 trillion by 2050 if we do not take action [2].
Therefore, worldwide actions are established to disprove the
hypothesis of Felix Marti-Ibanezin, already stated in 1955:
Antibiotic therapy, if indiscriminately used, may turn out to
be a medicinal flood that temporarily cleans and heals, but
ultimately destroy life itself [3].
The fact that hardly any new antimicrobial drugs have
been developed during the last decade has increased the
interest in Complementary and Alternative Medicine (CAM)
therapeutic interventions, if proven safe and effective. CAM
interventions can contribute to a reduction in antibiotic use
by (1) strengthening the self-healing capacities of the individ-
ual and/or (2) providing an alternative treatment which has
its own antimicrobial effect [4, 5].
In this paper the introduction of CAM in the future
control of AMR and examples of the evidence on CAM
alternatives are presented. A Dutch consortium of research
partners is initiated to (further) develop safe and effective
CAM alternatives to antibiotics.
2. Future Control of AMR
The environmental and policy factors that contribute to
resistance require regulatory and governmental intervention.
Therefore actions for future control are being taken to deter-
mine (research) and promote (education) appropriate use of
antimicrobial drugs on national and international basis.
Ongoing research is being performed to obtain evidence
for sophisticated molecular, immunologic, and microbial
techniques that will change the way infectious diseases are
diagnosed in the hope to reduce diagnostic uncertainty in
the next 2 decades [6]. Furthermore the development of new
vaccines might contribute to a decreased transmission and
impact of antimicrobial-resistant bacteria in the near future
as these vaccines might have the potential to effectively con-
trol infectious agents [7]. However, vaccine escape mecha-
nisms for bacteria have already been reported [8]. Variability
in parts of the genome coding for antigenic determinants,
such as in Bordetella pertussis (whooping cough), may lead to
a vaccine escape. In this way, despite vaccination, this DNA
variability contributed to reemergence of whooping cough in
the Netherlands.
National and international antimicrobial drug policies
and guidelines on infection control have been developed and
implemented resulting in a decrease of the volume of anti-
microbials over the past 10 years [9, 10]. Besides, national
campaigns to educate physicians and patients about the
appropriate use of antibiotics have been launched resulting in
promising changes in attitude among the public and health-
care professionals [11].
Whether the current epidemic of AMR is sustainable
or will succumb to the current efforts will also depend on
the worldwide healthcare regulation, as antimicrobial use is
affected by reimbursement policies, financial incentives, and
healthcare regulation [12].
However, even if the use of antibiotics was entirely appro-
priate resistance would still occur. Hence, the develop-
ment of new pharmaceuticals and antimicrobial agents is
essential and recommendations to facilitate development of
new antimicrobial agents are listed [13, 14]. One of these
recommendations is to increase the cooperation between
academia and industry for identifying potential targets.
Potential targets might be vaccination, surgical interventions,
awareness, and control of environmental risk factors, as well
as complementary and alternative medicine (CAM) [15].
3. Complementary and Alternative Medicine
Consumer interest in CAM has increased over the past
decade. Recent data indicate that a large proportion of the
population of developed countries, including Australia (52
69% of those surveyed), Canada (59-60%), the United States
(62%), Singapore (76%), and Japan (50%), has used CAM at
least once over a twelve-month period [16]. Between 20% and
80% of citizens in different EU countries have used CAM in
their healthcare [17]. In the Netherlands 15 percent of the total
population visits a CAM therapist yearly [18].
There are several explanations for the increasing use of
CAM services across the world. Earlier studies have suggested
that consumer dissatisfaction with conventional medication
may be a leading reason for CAM use [16]; however, more
recent reports indicate that an aspiration for active health-
care participation, greater disease chronicity and severity,
holistic healthcare beliefs, and increase in health awareness
behaviour are more likely to be associated with CAM use [19
21]. This suggests that complementary medicine is addressing
unmet needs in healthcare.
Due to the worldwide increasing use of CAM services,
the attention for safety, effectiveness, and cost-effectiveness of
CAM grows. A previous review [22] reported that some CAM
therapies are cost-effective compared with usual care for
various conditions. More recent results of two Dutch studies
demonstrated that patients whose general practitioner (GP)
practices CAM tend to have lower costs (10.1%) [23, 24].
The effectiveness of many CAM therapies has not been
proven in clinical trials yet [25]. Randomized controlled trials
(RCTs) are still considered and applied as the golden standard
for evaluation of effectiveness. However, RCTs may not
always be suitable for the evaluation of CAM, in particular,
to investigate the individual response treatment. The descrip-
tion of individual cases is probably the most important tool
for teaching in medicine, especially in CAM. However, most
of the times the information provided in single case reports
is not sufficient to provide sufficient evidence for effective-
ness [26]. Development of other methods for evaluation of
individual response instead of RCTs or adapted in RCTs is
necessary as it is essential that scientific evidence for CAM
will be established. In the best case, once scientific evidence
is there to prove a CAM therapy safe and effective and when
there is a clear working mechanism, the status can change
from CAM into conventional medicine.
Between January 2010 and December 2012, the CAM-
brella consortium has been looking into the current status of
CAM in Europe from different angles. Their findings stated
that future research methods must reflect the real-world
settings of healthcare in Europe and that everyone needs to
know in what situation CAM is a reasonable choice [27].
Therefore they recommend a clear emphasis on concurrent
Evidence-Based Complementary and Alternative Medicine
evaluation of CAM as an additional or alternative treatment
strategy in real-world settings. The strategy for the investiga-
tion of CAM should include a broad range of mixed-method
research strategies including comparative effectiveness
research and qualitative and quantitative designs. Stakehold-
ers such as citizens, patients, and providers should be closely
involved to ensure real-world relevance for the research [27].
4. CAM Alternatives to Antibiotics
CAM can contribute to a reduction in antibiotic use. On
the one hand, CAM therapies, which are proven safe, can be
used to strengthen the self-healing capacities of the organism
(preventive and curative health promotion) [4]. Here CAM is
an alternative for antibiotics but is not directly based on the
antimicrobial properties of the product itself. For example,
compared to conventional treatment, anthroposophic treat-
ment of primary care patients with acute respiratory and ear
symptoms had more favourable outcomes, lower antibiotic
prescription rates, less adverse drug reactions, and higher
patient satisfaction [28]. Moreover, the introduction of CAM
medicinal products might overcome the related side effects of
antibiotic use in childhood as several studies show that both
maternal and childs use of antibiotics were associated with an
increased risk of eczema or asthma [2931].
On the other hand, several (natural) medicinal products
as used in CAM can act as an alternative (fighting disease
strategies) to control infectious diseases based on their own
(bactericide or bacteriostatic) antimicrobial properties [5].
The development of conventional medicinal products and
CAM medicinal products such as those used in anthro-
posophic medicine, homeopathy, and traditional Chinese
medicine follow different pathways. Conventional medicinal
products are developed in the laboratory and subsequently
tested in preclinical studies, phases 13 clinical studies, and
finally in clinical practice. They are mostly used according
to a fixed schedule and for one indication. Conversely, CAM
medicinal products are developed in clinical practice with
regard to the principles of the respective medical system,
mostly have a long tradition of use, are often selected indi-
vidually to address the needs of each patient on the basis
of trained judgment skills of the health practitioner, and
are often used in combination with other (conventional)
medicinal products or nonpharmacological therapies. As a
result, CAM usually has multiple therapy options for each
indication [32].
Overall, there is much expert knowledge on CAM treat-
ment of infectious diseases but little scientific evidence based
on clinical trials. Currently there are 61 Cochrane reviews on
CAM treatments of specific infections (e.g., 29 on respiratory
tract infections). However, in most instances the quality of
clinical trials on CAM treatment of infections reviewed is
currently too low to provide sufficient evidence. Nevertheless,
some reviews and observational studies do demonstrate
positive and promising results.
For example, an observational study on anthroposophic
clinical practice demonstrates positive effects of treatment of
acute middle ear and upper respiratory infections (clinical
3
effects, patient satisfaction) in combination with small per-
centages of antibiotics prescription [28].
With regard to positive reviews, Echinacea is one of the
most widely used botanical supplements in North America
in the treatment of upper respiratory tract infections. One
review of 34 studies using Echinacea for the prevention of
upper respiratory tract infections showed that 22 had positive
outcomes [33]. Another review of nine RCTs showed that 8
reported some benefit of Echinacea in the early treatment of
upper respiratory infections [34].
The good antimicrobial properties of Abrus precatorius,
Terminalia phanerophlebia, Indigofera arrecta, and Pentanisia
prunelloides authenticate their traditional use in treatment of
respiratory diseases [35].
The increasing prevalence of isolates of Escherichia coli
(the most prevalent uropathogen) that are resistant to antimi-
crobial agents has stimulated interest in novel nonantibiotic
methods for prevention of urinary tract infections (UTIs).
Cranberries have been used in the prevention of UTIs for
many years. A meta-analysis of the results of two well-
performed RCTs showed that, in women with recurrent UTIs,
cranberry products reduced the incidence of recurrences at 12
months by 39% compared with placebo or control interven-
tions [36]. Beerepoot et al. reported that in premenopausal
women the use of antibiotics (TMP-SMX) is more effective
than cranberry capsules to prevent recurrent UTIs. However,
the use of TMP-SMX resulted in a considerable increase in
antibiotic resistance [37].
Another example is found in tackling antibiotic-resistant
strains of pathogens as Candida albicans. Candidiasis is a
benign mycosis resulting from a yeast infection caused by
Candida albicans. Candida albicans develops resistance to
regularly applied, standard antimycotic drugs such as clotri-
mazole, nystatin, fluconazole, and ketoconazole [38], and, as
a consequence, demand for prevention is high. Worldwide
several plant extracts have traditionally been used to prevent
Candidiasis [39]. The drawback with these treatments is that
they might interact with other medications if taken together
through changes in drug solubility and uptake, metabolism,
and physiology of the gastrointestinal tract [40]. This results
in adverse drug reactions such as allergic reactions, reduced
effects of contraceptives, and stomach damage [41]. Therefore
research to profile, detect, and screen alternatives among, for
example, plant compounds, which are effective in preventing
Candidiasis without these shortcomings, is needed.
5. Scientific Evidence as Key
Worldwide research in CAM is seriously hampered by a
lack of research infrastructure and funding, lack of research
expertise among CAM practitioners, lack of appropriate
research models and strategies, and the scepticism of the
conventional scientific community. In the USA, the national
authorities have taken the growing demand for CAM seri-
ously. The established National Centre for Complementary
and Alternative Medicine (NCCAM) in 1998 has already
funded 57 university based centres for research on CAM,
in contrast to Europe where only some western countries
4 Evidence-Based Complementary and Alternative Medicine
(Denmark, Germany, Norway, the UK, and the Netherlands)
have granted some money for research projects in CAM [42].
CAM research might contribute to controlling AMR and
in broader context to improving health, reducing disease,
and reducing healthcare related costs. However, the CAM
industry alone cannot be expected to support all research
activities in these areas. At the moment there is huge disparity
between public funding for conventional drug research and
that for CAM research.
Nowadays, national health authorities are asking for
effective actions to control AMR, and therefore the need for
sound clinical research (methods) to test the efficacy for CAM
strategies becomes more important. Clinicians using CAM in
daily routine practice, often resulting in nonuse or extended
use of antibiotics, are convinced about the effectiveness
of their services. However, before general acceptation and
introduction of these specific CAM alternatives first scientific
evidence is needed. Clearly, scientific evidence of CAM based
on sound clinical research methodology is the key to action.
6. The Introduction of a Consortium
The Professorships of Anthroposophic Healthcare, Biodiver-
sity, and Innovative Molecular Diagnostics of the University
of Applied Services of Leiden and the Louis Bolk Institute in
the Netherlands have taken the initiative to form a consor-
tium on scientific research on CAM and antibiotic resistance
(see Appendix). The aim and objective of the consortium is to
establish an enduring partnership and to develop expertise
to further develop and investigate safe and effective CAM
treatments for infectious diseases of humans (and animals).
The knowledge generated will lead to (1) evidence-based
CAM alternatives to antibiotics that can be used in clinical
practice and (2) guidelines for CAM treatments for infectious
diseases in human and veterinary clinical practice.
7. Description of First Project
A first project to find close relatives of species traditionally
used to prevent Candidiasis that could serve as safe biobased
antimycotics to be applied in registered medical sprays has
started (granted by the Naturalis tender application-oriented
research 2013). In short the study exists out of the following
activities:
(1) Instead of using random screening, a multistep tar-
geted approach is used that incorporates information
retrieved from museum collection labels to optimize
efficient species selection.
(a) Species across the angiosperms that have
uncomplicated European Medicines Agency
(EMA) regulations will be selected.
(b) Phylogenetic prospecting will be applied to
identify closely related species of interest.
(c) Crucial information of commercial interest, that
is, cultivation requirements and traditional use,
will be retrieved from metadata attached to
specimens, screened for legal constraints, and
applied in the prospecting.
(2) Extracts of living accessions from the profiled species
are being tested in antifungal and cellular assays.
(3) The most promising extract will be added to a regis-
tered medical device (using good manufacturing
practice guidelines) and will after ethics approval be
tested on safety and efficacy using a double blind-
placebo controlled trial design in clinical practice.
8. Conclusion
The increasing incidence of drug-resistant pathogens has
drawn the attention of the pharmaceutical and scientific com-
munities towards studies on the potential antimicrobial activ-
ity of CAM products and therapies. The aim of the introduced
Dutch CAM consortium is to provide evidence of safety, effi-
cacy, cost (effects), and modes of actions of CAM therapies,
which are useful as alternative strategies to control infectious
diseases and can become useful therapeutic tools in clinical
practice. The Dutch consortium will serve as a starting point
for further international collaboration with stakeholders
involved and/or interested in the study of CAM contributions
to the treatment of infections and the reduction of AMR.
Appendix
Composition of the Consortium
The consortium consists of the following parties:
(1) University of Applied Sciences Leiden (Hogeschool Lei-
den) participates with three professorships as follows:
(i) Anthroposophic Healthcare (Professor Dr. E. W.
Baars and Dr. E. T. Kok): it is able to cooperate
with the Louis Bolk Institute to perform clinical
studies to the safety and effects of (new) CAM
treatments in patients with infectious diseases.
The research group also has a large network
with anthroposophic care professionals includ-
ing doctors and nurses.
(ii) Biodiversity (Professor Dr. B. Gravendeel) and
Innovative Molecular Diagnostics (Professor Dr.
W. van Leeuwen): both research groups are able
to investigate the in vitro effects and safety of
(new) CAM treatments for infectious diseases.
(2) Louis Bolk Institute (Dr. M. C. Jong): it is able to
collaborate with the professorship of Anthroposophic
Healthcare to perform clinical studies to the safety
and effects of CAM treatments in patients with infec-
tious diseases. The institute also has a large network
with CAM practitioners in the Netherlands.
Abbreviations
AHI: Animal Health Institute
AMR: Antimicrobial resistance
CAHCIM: Consortium of Academic Health Centres for
Integrative Medicine
Evidence-Based Complementary and Alternative Medicine
CAM: Complementary and Alternative Medicine
CDC: Centres for Disease Control and
Prevention
EMA: European Medicines Agency
FDA: Food and Drug Administration
GP: General practitioner
IM: Integrative medicine
NCCAM: National Center for Complementary and
Alternative Medicine
WHO: World Health Organization.
Disclosure
This study was conducted as part of the authors routine work.
Conflict of Interests
The authors declare that there is no conflict of interests
regarding the publication of this paper.
References
[1] W. McDermott and D. E. Rogers, Social ramifications of con-
trol of microbial disease, Johns Hopkins Medical Journal, vol.
151, no. 6, pp. 302312, 1982.
[2] J. ONeil, Review on Antimicrobial Resistance. Antimicrobial
Resistance: Tackling a Crisis for the Health and Wealth of Nations,
WEST, 2014.
[3] R. E. McFayden, The FDAs regulation and control of antibi-
otics in the 1950s: the Henry Welch scandal, Felix Mart-Iban ez,
and Charles Pfizer & Co, Bulletin of the History of Medicine, vol.
53, no. 2, pp. 159169, 1979.
[4] P. Heusser, Ed., Akademische Forschung in der Anthroposophis-
chen Medizin. Beispiel Hygiogenese: Natur- und geisteswis-
senschaftliche Zugange zur Selbstheilungskraft des Menschen,
Peter Lang, Bern, Switzerland, 1999.
[5] P. Heusser, Physiologische grundlagen der gesundheitsford-
erung und das anthroposophisch-medizinische Konzept, in
Gesundheitsforderung- eine neue Zeitforderung Interdisziplinare
Forschung und Beitrag der Komplementarmedizin, P. Heusser,
Ed., vol. 6, pp. 101129, Peter Lang, Bern, Switzerland, 2002.
[6] D. Raoult, P. E. Fournier, and M. Drancourt, What does the
future hold for clinical microbiology? Nature Reviews Microbi-
ology, vol. 2, no. 2, pp. 151159, 2004.
[7] F. A. Waldvogel, Infectious diseases in the 21st century: old
challenges and new opportunities, International Journal of
Infectious Diseases, vol. 8, no. 1, pp. 512, 2004.
[8] F. R. Mooi, I. H. M. van Loo, and A. J. King, Adaptation of
Bordetella pertussis to vaccination: a cause for its reemergence?
Emerging Infectious Diseases, vol. 7, no. 3, pp. 526528, 2001.
[9] S. Molstad, C. S. Lundborg, A.-K. Karlsson, and O. Cars, Anti-
biotic prescription rates vary markedly between 13 European
countries, Scandinavian Journal of Infectious Diseases, vol. 34,
no. 5, pp. 366371, 2002.
[10] D. M. Patrick, F. Marra, J. Hutchinson, D. L. Monnet, H. Ng,
and W. R. Bowie, Per capita antibiotic consumption: how does
a North American jurisdiction compare with Europe? Clinical
Infectious Diseases, vol. 39, no. 1, pp. 1117, 2004.
[11] http://www.cdc.gov/.
5
[12] S. Harbarth, W. Albrich, and C. Brun-Buisson, Outpatient
antibiotic use and prevalence of antibiotic-resistant pneumo-
cocci in France and Germany: a sociocultural perspective,
Emerging Infectious Diseases, vol. 8, no. 12, pp. 14601467, 2002.
[13] S. R. Norrby, C. E. Nord, and R. Finch, Lack of development
of new antimicrobial drugs: a potential serious threat to public
health, Lancet Infectious Diseases, vol. 5, no. 2, pp. 115119, 2005.
[14] E. Larson, Community factors in the development of antibiotic
resistance, Annual Review of Public Health, vol. 28, pp. 435447,
2007.
[15] L. N. Werk and H. Bauchner, Practical considerations when
treating children with antimicrobials in the outpatient setting,
Drugs, vol. 55, no. 6, pp. 779790, 1998.
[16] M. J. Leach, Public, nurse and medical practitioner attitude
and practice of natural medicine, Complementary Therapies in
Nursing and Midwifery, vol. 10, no. 1, pp. 1321, 2004.
[17] http://www.efcam.eu.
[18] http://www.cbs.nl.
[19] A. Busato, A. Donges, S. Herren, M. Widmer, and F. Marian,
Health status and health care utilisation of patients in com-
plementary and conventional primary care in Switzerland-an
observational study, Family Practice, vol. 23, no. 6, pp. 116124,
2006.
[20] F. M. Sirois and R. J. Purc-Stephenson, Consumer decision
factors for initial and long-term use of complementary and
alternative medicine, Complementary Health Practice Review,
vol. 13, no. 1, pp. 319, 2008.
[21] A. M. Vlieger, M. van Vliet, and M. C. Jong, Attitudes toward
complementary and alternative medicine: a national survey
among paediatricians in the Netherlands, European Journal of
Pediatrics, vol. 170, no. 5, pp. 619624, 2011.
[22] P. M. Herman, B. M. Craig, and O. Caspi, Is complementary
and alternative medicine (CAM) cost-effective? A systematic
review., BMC Complementary and Alternative Medicine, vol. 5,
article 11, 2005.
[23] P. Kooreman and E. W. Baars, Patients whose GP knows
complementary medicine tend to have lower costs and live
longer, European Journal of Health Economics, vol. 13, no. 6, pp.
769776, 2012.
[24] P. Kooreman and E. W. Baars, A 6-year comparative economic
evaluation of healthcare costs and mortality rates of Dutch
patients from conventional and CAM GPs, BMJ Open, vol. 4,
no. 8, Article ID e005332, 2014.
[25] S. Singh and E. Ernst, Trick or Treatment: The Undeniable Facts
about Alternative Medicine, W.W. Norton & Company, New
York, NY, USA, 2008.
[26] M. Teut and K. Linde, Scientific case research in comple-
mentary and alternative medicine-a review, Complementary
Therapies in Medicine, vol. 21, no. 4, pp. 388395, 2013.
[27] CAMbrella, The Roadmap to European CAM Research An
Explanation of the CAMbrella Project and Its Key Findings,
CAMbrella, 2012.
[28] H. J. Hamre, M. Fischer, M. Heger et al., Anthroposophic vs.
conventional therapy of acute respiratory and ear infections: a
prospective outcomes study, Wiener Klinische Wochenschrift,
vol. 117, no. 7-8, pp. 256268, 2005.
[29] E. Goksor, B. Alm, R. Pettersson et al., Early fish introduction
and neonatal antibiotics affect the risk of asthma into school
age, Pediatric Allergy and Immunology, vol. 24, no. 4, pp. 339
344, 2013.
 6 Evidence-Based Complementary and Alternative Medicine

[30] M. Muc, C. Padez, and A. M. Pinto, Exposure to paracetamol

and antibiotics in early life and elevated risk of asthma in
childhood, Advances in Experimental Medicine and Biology,
vol. 788, pp. 393400, 2013.
[31] T. Tsakok, T. M. McKeever, L. Yeo, and C. Flohr, Does early life
exposure to antibiotics increase the risk of eczema? A systematic
review, British Journal of Dermatology, vol. 169, no. 5, pp. 983
991, 2013.
[32] G. S. Kienle, H.-U. Albonico, L. Fischer et al., Complementary
therapy systems and their integrative evaluation, Explore, vol.
7, no. 3, pp. 175187, 2011.
[33] D. Melchart, E. Walther, K. Linde, R. Brandmaier, and C. Lersch,
Echinacea root extracts for the prevention of upper respiratory
tract infections: a double-blind, placebo-controlled randomized
trial, Archives of Family Medicine, vol. 7, no. 6, pp. 541545, 1998.
[34] B. Barrett, M. Vohmann, and C. Calabrese, Echinacea for upper
respiratory infection, Journal of Family Practice, vol. 48, no. 8,
pp. 628635, 1999.
[35] B. Madikizela, A. R. Ndhlala, J. F. Finnie, and J. V. Staden,
In vitro antimicrobial activity of extracts from plants used
traditionally in South Africa to treat tuberculosis and related
symptoms, Evidence-Based Complementary and Alternative
Medicine, vol. 2013, Article ID 840719, 8 pages, 2013.
[36] R. G. Jepson and J. C. Craig, Cranberries for preventing urinary
tract infections, Cochrane Database of Systematic Reviews,
Article ID CD001321, 2008.
[37] M. A. J. Beerepoot, G. Ter Riet, S. Nys et al., Cranberries vs
antibiotics to prevent urinary tract infections: a randomized
double-blind noninferiority trial in premenopausal women,
Archives of Internal Medicine, vol. 171, no. 14, pp. 12701278, 2011.
[38] M. Gv, A general overwie on past, present and future antimy-
cotics, The Open Mycology Journal, vol. 4, pp. 2232, 2010.
[39] J. F. Hofling, R. C. Mardegan, P. C. Anibal, V. F. Furletti, and
M. A. Foglio, Evaluation of antifungal activity of medicinal
plant extracts against oral Candida albicans and proteinases,
Mycopathologia, vol. 172, no. 2, pp. 117124, 2011.
[40] M. Pirmohamed, Drug-grapefruit juice interactions: two
mechanisms are clear but individual responses vary, British
Medical Journal, vol. 346, article f1, 2013.
[41] A. Aboellil and M. Al-Tuwaijri, Effect of some alternative
medicine and biological factors on Candida albicans in Saudi
Arabia, Journal of Yeast and Funfal Research, vol. 1, pp. 100107,
2010.
[42] https://nccih.nih.gov/.